title: Inhibition of dehydroepiandosterone sulfate action in androgen-sensitive tissues by EM-1913, an inhibitor of steroid sulfatase.
abstract: Steroid sulfatase (STS) plays an important role in the formation of estrogens and androgens by allowing the conversion of inactive circulating sulfated steroids into active hormones. These steroids support the development and growth of a number of hormone-dependent cancers, including prostate cancer. Here, we tested a non-estrogenic and non-androgenic inhibitor of steroid STS, namely EM-1913, with special attention to its potential use in the treatment of prostate cancer. After determining the required dosage of dehydroepiandrosterone sulfate (DHEAS) needed to stimulate the ventral prostate and seminal vesicles in castrated rats, we measured that EM-1913 partially (26%) and almost entirely blocked (81%) the stimulating effect of DHEAS on ventral prostates and seminal vesicles, respectively. In addition, the homogenization of these two tissues allowed us to confirm that they were completely deprived of STS activity following a treatment with EM-1913. This effect is also reflected in blood, since the plasma level of DHEAS was increased in animals treated with EM-1913, whereas the levels of dehydroepiandrosterone (DHEA) and dihydrotestosterone (DHT), two DHEAS metabolites, meanwhile decreased. From these results, we concluded that STS inhibitor EM-1913 is a good candidate for additional preclinical studies.
authors.affiliation: Laboratory of Medicinal Chemistry, CHU de Québec - Research Center Endocrinology and Nephrology Unit and Faculty of Medicine, Université Laval, Québec, Canada.
authors.forename: Jenny
authors.initials: J
authors.lastname: Roy
authors.forename: Julie
authors.initials: J
authors.lastname: Lefebvre
authors.forename: René
authors.initials: R
authors.lastname: Maltais
authors.forename: Donald
authors.initials: D
authors.lastname: Poirier
mesh_terms: D000818:Animals; D003687:Dehydroepiandrosterone / Q000097:blood; D019314:Dehydroepiandrosterone Sulfate / Q000037:antagonists & inhibitors / Q000097:blood / Q000494:pharmacology*; D013196:Dihydrotestosterone / Q000097:blood; D004791:Enzyme Inhibitors / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D004958:Estradiol / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D009919:Orchiectomy; D011467:Prostate / Q000187:drug effects* / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012669:Seminal Vesicles / Q000187:drug effects* / Q000201:enzymology; D043266:Steryl-Sulfatase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C586249:EM-1913; D004791:Enzyme Inhibitors; D013196:Dihydrotestosterone; D003687:Dehydroepiandrosterone; D004958:Estradiol; D019314:Dehydroepiandrosterone Sulfate; D043266:Steryl-Sulfatase
keywords: Androgen; Enzyme inhibitor; Hormone; Prostate cancer; Steroid; Steroid sulfatase